This proposed Program will use prospectively collected dietary data and frozen plasma and DNA specimens to address a series of hypotheses regarding major cancers in men and women. In addition, these nutritional and genetic exposures will be examined in relation to specific molecular characteristics of tumors. The cancers to be studied are those of the prostate, colon and rectum, bladder, lung, kidney, and ovary. This Program Project supports, and depends on, the continued follow-up of 51,529 men who completed an extensive dietary questionnaire first in 1986 and again in 1990, 1994, and 1998 (the Health Professional?s Follow-up Study, HPFS), and is also closely linked to the Nurses? Health Study (NHS) of 121,700 women. The Program Project has already contributed substantially to information on diet and cancers of the breast, prostate, colon, and bladder. The proposed continuation will extend and refine observations from the first twelve years of follow-up and will also address new hypotheses related to both cancer incidence and survival. Project 1 will examine dietary (lycopene, calcium, and N-3 fatty acid intakes) and other predictors of prostate cancer incidence in relation to risk of PSA relapse among men with apparently successful treatment for localized prostate cancer. In addition, a series of dietary and hormonal factors will be related to specific characteristics of incident cancers, including expression of PTEN and COX-2 and markers of angiogenesis. Project 2 will address hypotheses relating intakes of folic acid, calcium and red meat and plasma levels of IGF-1 and its binding proteins to risks of both colorectal cancer and adenomas. Interactions with germline polymorphisms and relationships with specific molecular tumor characteristics will be examined. Project 5 will examine dietary and related risk factors for bladder cancer in both men and women. Exposures will include intakes of cruciferous vegetables and total fluids, and biochemical indicators of selenium and arsenic exposure. Interactions with polymorphisms in carcinogen metabolizing genes and specific association with p53 expression in tumors will also be examined. Project 4 pools data from all eleven major published prospective studies of diet and cancer. Precise and unique information has already been obtained for breast, lung and colon cancers, and the proposed work will extend analyses to cancers of the pancreas and ovary. These highly interrelated studies that integrate dietary factors, established non-dietary risk factors, endogenous hormone levels, genetic susceptibility, and molecular characteristics of tumors, will contribute importantly to the understanding and prevention of the major cancers of men and women.